API SYNTHESIS INTERNATIONAL: PRANIDIPINE

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Showing posts with label PRANIDIPINE. Show all posts

Sunday, 13 December 2015

PRANIDIPINE

Pranidipine , OPC-13340, FRC 8411

Acalas^®

A calcium channel blocker potentially for the treatment of angina pectoris and hypertension.

CAS No. 99522-79-9

Molecular FormulaC₂₅H₂₄N₂O₆
Average mass448.468

methyl (2E)-3-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Methyl-(2E)-3-phenyl-2-propen-1-yl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridindicarboxylat (E)-Cinnamyl methyl (±)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate

Methyl cinnamyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate

trans-Cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

3,5-Pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, methyl (2E)-3-phenyl-2-propen-1-yl ester

Pranidipine is a calcium channel blocker. It is a long acting calcium channel antagonist of the dihydropyridine group.^[1]

PATENT

EP 0173126 http://www.google.com/patents/EP0173126A1?cl=en

PAPER

Der Pharmacia Sinica, 2014, 5(1):11-17

pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf

CLICK ON IMAGE FOR CLEAR VIEW

Preparation of Pranidipine Hydrochloride(2):

To a suspension of (Z)-2-(3-nitrobenzylidene)-3-oxobutanoic acid(3) (1.2 kg, 5.10 mol) in dichloromethane (6 L)

was added triethylamine(0.77 kg, 7.65 mol) and cinnamyl chloride (0.85 kg, 5.61 mol). The reaction mixture was

heated to 45°C and maintained for 2 hrs. The suspension was cooled to 25 to 30°C and washed with 2.4 Lof DM

water. DCM layer was separated and concentrated under vacuum below 40°C. The concentrated mass was dissolved

in 7.2 L isopropyl alcohol and methyl-3-amino crotonate (0.52 kg, 4.5mol) was added to it. Temperatureof reaction

mixture was slowly raised to 70°C and maintained for 8 hours. Reaction mass was concentrated under vacuum

below 40°C.To the crude residue, ethyl acetate-HCl(0.28 kg, 7.6 mol) was added and the reaction mixture was

stirred for 24 hours at 25°C-30°C. Reaction mixturewas filtered and the solid residue was dried under

vacuum toafford 1.6 kg of Pranidipine hydrochloride (2)in 85% yield with 98 % purity.

1H-NMR(DMSO):

δ2.29 (s, 3H),2.32 (s, 3H), 3.55 (s, 3H), 4.60-4.74 (m, 2H), 5.04(s, 1H), 6.26-6.33 (m, 1H), 6.50 (d, 1H), 7.24-7.3

8 (m, 5H), 7.53(t, 1H), 7.63 (d,1H), 7.98-8.01 (m, 1H), 9.08 (brs, 1H)

Preparation of (Z)-2-(3-nitrobenzylidene)-3-oxobutanoic acid(3):

To a suspension of (Z)-t-butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10) (1.5 kg, 5.14 mol) in dichloromethane

(7.5 L) was added trifluoroacetic acid (1.76 kg, 15.44 mol) and reaction mass was stirred at 25°C to 30°C for 24 hrs.

The reaction mass was concentrated under vacuum below 40°C and stripped with toluene. The concentratedmass

was dissolved in 4.5 L toluene and the solution wasstirred for 8 hours at 25°C to 30°C. Reaction mixture was

filtered and solid washed with toluene and dried at35°C to 40°C to give 1.152 kg of (Z)-2-(3-nitrobenzylidene)-3-

oxobutanoic acid(3) in 96 % yield. M.P: 120°C; Mol.Wt: 235.20; Mol.Formula: C11H9NO5;1H-NMR(DMSO):

δ2.46 (s, 3H), 7.76-7.83 (m, 2H), 8.02 (d, 1H), 8.28-8.31 (dd, 1H), 8.51 (s, 1H), 13.63 (brs, 1H).Anal.Calcd for

C11H10NO5 : C, 55.93; H, 4.27; N, 5.93. Found: C, 56.19;H, 4.09; N, 6.27

Preparation of (Z)-tertiary- butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10):

To a suspension of 3-nitrobenzaldehyde(5) (1 kg, 6.61 mol) in isopropyl alcohol (6 L) was addedt-butylacetoacetate (1.14 kg, 7.27 mol),piperidine (0.12 kg, 1.32 mol) and acetic acid (0.79 kg, 1.32 mol). The reactionmass was stirred at 25°C to 30°C for 6 hrs. The suspension was cooled to -5 to 0°C, filtered, residuewashed withisopropyl alcohol and dried at 35°C to 40°C to give

1.750 kg of (Z)-t-butyl 2-(3-nitrobenzylidene)-3-oxobutanoate(10)in 91% yield; M.P: 80°C; Mol. Wt: 291.31; Mol.Formula: C15H17NO5

1H-NMR(CDCl3):

δ1.55(s, 9H), 2.44 (s, 3H), 7.50 (s, 1H),7.59 (t, 1H),7.80 (d, 1H), 8.24- 8.27 (dd,J=1H),δ8.41 (t, 1H).

CLICK ON IMAGE FOR CLEAR VIEW

Patent	Submitted	Granted
Process for the preparation of 1,4 - dihydropyridines and novel 1,4-dihydropyridines useful as therapeutic agents [US2003230478]	2003-12-18
Advanced Formulations and Therapies for Treating Hard-to-Heal Wounds [US2014357645]	2014-08-19	2014-12-04
METHODS OF TREATING CARDIOVASCULAR AND METABOLIC DISEASES [US2014322199]	2012-08-06	2014-10-30
Protein Carrier-Linked Prodrugs [US2014323402]	2012-08-10	2014-10-30
sGC STIMULATORS [US2014323448]	2014-04-29	2014-10-30
TREATMENT OF ARTERIAL WALL BY COMBINATION OF RAAS INHIBITOR AND HMG-CoA REDUCTASE INHIBITOR [US2014323536]	2012-12-07	2014-10-30
Agonists of Guanylate Cyclase Useful For the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders [US2014329738]	2014-03-28	2014-11-06
METHODS, COMPOSITIONS, AND KITS FOR THE TREATMENT OF CANCER [US2014335050]	2012-05-25	2014-11-13
ROR GAMMA MODULATORS [US2014343023]	2012-09-18	2014-11-20
High-Loading Water-Soluable Carrier-Linked Prodrugs [US2014296257]	2012-08-10	2014-10-02

Publication Number

Publication Date

IPCR Assignee/Applicant

Structure hits

Tools

US-20150342954-A1

2015-12-03

A61K 31/52

IRONWOOD PHARMACEUTICALS INC

2-BENZYL, 3-(PYRIMIDIN-2-YL) SUBSTITUTED PYRAZOLES USEFUL AS SGC STIMULATORS

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

EP-2558474-B1

2015-11-25

C07D 498/04

RIGEL PHARMACEUTICALS INC

2, 4-PYRIMIDINEDIAMINE COMPOUNDS AND PRODRUGS THEREOF AND THEIR USES

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

US-20150307580-A1

2015-10-29

C07K 14/605

MERCK SHARP & DOHME

OXYNTOMODULIN ANALOGS

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

US-20150305974-A1

2015-10-29

A61H 23/02

SYMPARA MEDICAL INC

METHODS AND DEVICES FOR TREATING HYPERTENSION

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

WO-2015164658-A1

2015-10-29

A61H 23/00

SYMPARA MEDICAL INC

METHODS AND DEVICES FOR TREATING HYPERTENSION

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

EP-2527360-B1

2015-10-28

C07K 7/08

SYNERGY PHARMACEUTICALS INC

Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

WO-2015157471-A1

2015-10-15

A61K 31/198

METHODIST HOSPITAL

INOS-INHIBITORY COMPOSITIONS AND THEIR USE AS BREAST CANCER THERAPEUTICS

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

US-20150284411-A1

2015-10-08

C07D 519/00

APGAR JAMES M

NOVEL AZABENZIMIDAZOLE HEXAHYDROFURO[E,2-B]FURAN DERIVATIVES

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

US-20150283202-A1

2015-10-08

A61K 38/10

SYNERGY PHARMACEUTICALS INC

AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF HYPERCHOLESTEROLEMIA, ATHEROSCLEROSIS, CORONARY HEART DISEASE, GALLSTONE, OBESITY AND OTHER CARDIOVASCULAR DISEASES

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

10.

US-9150512-B2

2015-10-06

C07D 209/64

JANSSEN PHARMACEUTICA NV

Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

$COC(=O)C1=C(C)NC(C)=C(C1C1=CC(=CC=C1)[N+]([O-])=O)C(=O)OC\C=C\C1=CC=CC=C1$

References

Jin Yang, Keisuke Fukuo, Shigeto Morimoto, Tadaaki Niinobu, Toshimitsu Suhara, Toshio Ogihara (2000). "Pranidipine Enhances the Action of Nitric Oxide Released From Endothelial Cells". Hypertension 35: 82–85. doi:10.1161/01.hyp.35.1.82. http://pelagiaresearchlibrary.com/der-pharmacia-sinica/vol5-iss1/DPS-2014-5-1-11-17.pdf.........NICARDIPINE

Pranidipine
Names

IUPAC name methyl (2E)-phenylprop-2-en-1-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Other names 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid O⁵-methyl O³-[(E)-3-phenylprop-2-enyl] ester
Identifiers
CAS Number	99522-79-9
ChEMBL	ChEMBL1096842
ChemSpider	4940726
InChI [show]
Jmol interactive 3D	Image
MeSH	C048161
PubChem	6436048
SMILES [show]
UNII	9DES9QVH58
Properties
Chemical formula	C₂₅H₂₄N₂O₆
Molar mass	448.46786